Shirley X. Yan

Computer-Assisted Diagnosis of Lung Cancer Using Quantitative Topology Features

In this paper, we proposed a computer-aided diagnosis and analysis for a challenging and important clinical case in lung cancer, i.e., differentiation of two subtypes of Non-small cell lung cancer NSCLC. The proposed framework utilized both local and topological features from histopathology images. To extract local features, a robust cell detection and segmentation method is first adopted to segment each individual cell in images. Then a set of extensive local features is extracted using efficient geometry and texture descriptors based on cell detection results. To investigate the effectiveness of topological features, we calculated architectural properties from labeled nuclei centroids. Experimental results from four popular classifiers suggest that the cellular structure is very important and the topological descriptors are representative markers to distinguish between two subtypes of NSCLC.

Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis

Patients with multiple sclerosis (MS) show a high prevalence of myelin-reactive CD8+ and CD4+ T-cell responses, which are the putative effectors/modulators of CNS neuropathology. Utilizing a novel combination of short-term culture, CFSE-based sorting and anchored PCR, we evaluated clonal compositions of neuroantigen-targeting T-cells from RRMS patients and controls. CDR3 region analysis of TCRβ chains revealed biased use of specific TCRBV-bearing CD4+ clones. CD8+ clones showed homology to published TCR from CNS-infiltrating T-cells in MS lesions. These studies are the first description of TCR usage of CNS-specific CD8+ T-cells and provide insights into their potential regulatory role in disease.

Response to Crizotinib/Erlotinib Combination in a Patient with a Primary EGFR-Mutant Adenocarcinoma and a Primary c-met–Amplified Adenocarcinoma of the Lung

Targeted therapy has become a valuable approach in adenocarcinoma of the lung. The number of actionable mutations has been continuously increasing with significant acceleration from discovery to clinical application. Herein, we present a case of innovative treatment using targeted therapy of a 75-year-old female with two primary adenocarcinomas of the lung. The first tumor was found to carry an activating mutation in the exon 19 of the epidermal growth factor receptor and responded favorably to treatment with erlotinib. The second primary tumor was found to carry an isolated amplification of the c-met gene but no epidermal growth factor receptor mutation. Off-label use of crizotinib, a potent inhibitor of c-met, was prescribed. Within 4 weeks of treatment initiation, the tumor and the dependent lymphadenopathy responded with rapid shrinkage. This observation stresses the need for rebiopsy of tumors upon progression or change of biological behavior for selection of appropriate targeted therapy.

Solid pseudopapillary neoplasm collides with a well-differentiated pancreatic endocrine neoplasm in an adult man: case report and review of histogenesis.

OBJECTIVES Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, clinicopathologically distinct neoplasm with a tendency to affect young women. The histogenesis of SPN is not well defined. Pancreatic endocrine neoplasms (PENs) are also uncommon tumors of the pancreas. METHODS Our comprehensive review of the literature did not yield any reported cases of collision tumors of the above two neoplasms. We report a case of such a collision tumor in a 45-year-old man. RESULTS This tumor was an incidental finding on computed tomography, followed by fine-needle aspiration confirmation of a tumor that was initially diagnosed as an SPN only. A histologic examination of a 2.1-cm mass following distal pancreatectomy revealed a 0.7-cm PEN partly engulfed by an SPN. The tumors showed different morphologic and immunohistochemical features, confirming the presence of a collision tumor. CONCLUSIONS A comparative analysis of immunoprofiles of these tumors yielded interesting findings, enabling us to postulate that SPNs may originate from a multipotential primordial cell that may follow different differentiation pathways, such as endocrine, epithelial, and acinar. The ultrastructures and immunophenotypic characteristics appear to support this hypothesis.

Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice

C-reactive protein (CRP), was recently reported to be closely associated with poor renal function in patients with acute kidney injury (AKI), but whether CRP is pathogenic or a mere biomarker in AKI remains largely unclear. Impaired autophagy is known to exacerbate renal ischemia-reperfusion injury (IRI). We examined whether the pathogenic role of CRP in AKI is associated with reduction of autophagy. We mated transgenic rabbit CRP over-expressing mice (Tg-CRP) with two autophagy reporter mouse lines, Tg-GFP-LC3 mice (LC3) and Tg-RFP-GFP-LC3 mice (RG-LC3) respectively to generate Tg-CRP-GFP-LC3 mice (PLC3) and Tg-CRP-RFP-GFP-LC3 mice (PRG-LC3). AKI was induced by IRI. Compared with LC3 mice, PLC3 mice developed more severe kidney damage after IRI. Renal tubules were isolated from LC3 mice at baseline for primary culture. OKP cells were transiently transfected with GFP-LC3 plasmid. CRP addition exacerbated lactate dehydrogenase release from both cell types. Immunoblots showed lower LC-3 II/I ratios and higher levels of p62, markers of reduced autophagy flux, in the kidneys of PLC3 mice compared to LC3 mice after IRI, and in primary cultured renal tubules and OKP cells treated with CRP and H2O2 compared to H2O2 alone. Immunohistochemistry showed much fewer LC-3 punctae, and electron microscopy showed fewer autophagosomes in kidneys of PLC3 mice compared to LC3 mice after IRI. Similarly, CRP addition reduced GFP-LC3 punctae induced by H2O2 in primary cultured proximal tubules and in GFP-LC3 plasmid transfected OKP cells. Rapamycin, an autophagy inducer, rescued impaired autophagy and reduced renal injury in vivo. In summary, it was suggested that CRP be more than mere biomarker in AKI, and render the kidney more susceptible to ischemic/oxidative injury, which is associated with down-regulating autophagy flux.

High-Risk and Poorly Differentiated Thyroid Cancer

Follicular cell-derived thyroid carcinomas are classified based on their histology and cellular architecture, as well differentiated (papillary carcinoma and follicular carcinoma), poorly differentiated, and undifferentiated thyroid carcinomas (Pathology and genetics of tumors of endocrine organs. Lyon: IARC Press, 2004). Although the majority of clinically diagnosed thyroid cancers today are of the well-differentiated variety arising from follicular thyroid cells, dedifferentiation results in an aggressive phenotype which is responsible for an inordinate number of deaths from thyroid cancer.

Glucocorticoid-responsive lymphocytic parathyroiditis and hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor: a case report and literature review

OBJECTIVE Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with autoantibodies against the calcium-sensing receptor (anti-CaSR) are rare and poorly understood conditions. Here, we describe a patient with acquired parathyroid hormone (PTH)-dependent hypercalcemia with associated hypocalciuria, found to have true lymphocytic parathyroiditis on histopathology, and circulating anti-CaSR antibodies in serum. DESIGN AND METHODS A 64-year-old woman was referred to our clinic for persistent hypercalcemia after a subtotal parathyroidectomy. She was normocalcemic until the age of 63 years when she was diagnosed with primary hyperparathyroidism. She underwent subtotal parathyroidectomy with appropriate intraoperative PTH decline. Two weeks post-parathyroidectomy, she presented with persistent hypercalcemia and hyperparathyroidism. Urine studies revealed an inappropriately low 24-h urine calcium (Ca)/creatinine clearance ratio. Surgical pathology was consistent with true lymphocytic parathyroiditis with lymphoid follicles. The presence of circulating anti-CaSR antibodies was detected by immunoprecipitation of CaSR by the patients serum. After a 4-week course of prednisone, serum Ca and PTH normalized, and her anti-CaSR titers declined. She remains normocalcemic 10 months after the discontinuation of glucocorticoid therapy. We present this patient in the context of the relevant published literature on lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia related to anti-CaSR antibodies. CONCLUSIONS Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with anti-CaSR antibodies is a very rare yet important condition to be considered in a patient with acquired PTH-dependent hypercalcemia with inappropriate hypocalciuria. Although subtotal parathyroidectomy is unlikely to correct the hypercalcemia, this entity may respond to a short course of prednisone therapy.